Role of epithelial-mesenchymal transition in stem cell differentiation and tumorigenesis

doi:10.3969/j.issn.2095-4344.2017.17.021

Chinese Journal of Tissue Engineering Research ›› 2017, Vol. 21 ›› Issue (17): 2753-2758.doi: 10.3969/j.issn.2095-4344.2017.17.021

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Role of epithelial-mesenchymal transition in stem cell differentiation and tumorigenesis

Zhang Feng-bo^{1, 2, 3, 4}, Li Ling-li^{1, 2, 3, 4}, Jiang Xin-xing^{2, 3, 4}, Ma Yan-Lin^{1, 2, 3, 4}, Li Qi^{1, 2, 3, 4}

¹Hainan Medical University, Haikou 571199, Hainan Province, China; ²Affiliated Hospital of Hainan Medical University, Haikou 571199, Hainan Province, China; ³Hainan Provincial Key Laboratory for Human Reproductive Medicine and Genetic Research, Haikou 571199, Hainan Province, China; ⁴the Key Laboratory of Tropical Diseases and Translational Medicine of The Ministry of Education, Haikou 571199, Hainan Province, China

Revised:2017-01-07 Online:2017-06-18 Published:2017-06-29
Contact: Li Qi, Researcher, Hainan Medical University, Haikou 571199, Hainan Province, China; Affiliated Hospital of Hainan Medical University, Haikou 571199, Hainan Province, China; Hainan Provincial Key Laboratory for Human Reproductive Medicine and Genetic Research, Haikou 571199, Hainan Province, China; the Key Laboratory of Tropical Diseases and Translational Medicine of the Ministry of Education, Haikou 571199, Hainan Province, China
About author:Zhang Feng-bo, Studying for master’s degree, Hainan Medical University, Haikou 571199, Hainan Province, China; Affiliated Hospital of Hainan Medical University, Haikou 571199, Hainan Province, China; Hainan Provincial Key Laboratory for Human Reproductive Medicine and Genetic Research, Haikou 571199, Hainan Province, China; the Key Laboratory of Tropical Diseases and Translational Medicine of the Ministry of Education, Haikou 571199, Hainan Province, China
Supported by:
the National Natural Science Foundation of China, No. 81460034, 81060175; the National Special Project of International Cooperation in Science and Technology, the Ministry of Science and Technology of China, No. 2014DFA30180; the Natural Science Foundation of Hainan Province, No. 812201; the Undergraduate Innovative Research Project of Hainan Provincial High Educations, No. Hys 2015-61

Abstract

Abstract:

BACKGROUND: Epithelial-mesenchymal transition is closely related to embryonic development, stem cell-induced differentiation, injury tissue repair and tumorigenesis.
OBJECTIVE: To review the role of epithelial-mesenchymal transition in stem cell differentiation and tumorigenesis.
METHODS: The CNKI and PubMed databases were retrieved by computer for relevant literatures published from 2001 to 2016 with the key words of “epithelial-mesenchymal transition, stem cell, tumor/cancer” in Chinese and English, respectively. 1 249 articles were retrieved in total, and 50 papers were suitable for final analysis.
RESULTS AND CONCLUSION: The epithelial-mesenchymal transition is closely associated with stem cell differentiation, tumorigenesis and tumor progression. The emergence of epithelial-mesenchymal transition related markers were found in stem cell differentiation and tumor invasion and metastasis. Epithelial-mesenchymal transition is affected by a variety of regulatory factors, and the differentiation of stem cells and the occurrence and development of tumor are also multi-procedural and multi-step complex processes. Although we have a more thorough understanding on occurrence mechanisms and some regulation mechanisms of epithelial-mesenchymal transition for stem cell differentiation and tumorigenesis, the understanding of the complex regulatory network is still not enough. How to have a deeper understanding of the occurrence and regulation mechanisms of epithelial-mesenchymal transition, and how to apply research results safely and effectively in the clinical prevention, diagnosis and treatment will be the common goal of us now and in the future.

中国组织工程研究杂志出版内容重点：干细胞；骨髓干细胞；造血干细胞；脂肪干细胞；肿瘤干细胞；胚胎干细胞；脐带脐血干细胞；干细胞诱导；干细胞分化；组织工程

Key words: Stem Cells, Neoplasms, Tissue Engineering

CLC Number:

R318

Zhang Feng-bo, Li Ling-li, Jiang Xin-xing, Ma Yan-Lin, Li Qi. Role of epithelial-mesenchymal transition in stem cell differentiation and tumorigenesis[J]. Chinese Journal of Tissue Engineering Research, 2017, 21(17): 2753-2758.

Figures/Tables 1

2.1 上皮间质转化概述上皮间质转化最早是被发育生物学家用来描述胚胎发育过程中某些特定部位的上皮细胞所发生的形态学和特性改变，使其在生物学上更适合侵袭和转移[9]。上皮间质转化可发生在多种生理及病理状况下，在上皮间质转化过程中上皮细胞功能特性和细胞骨架结构发生了改变，包括：细胞间黏附分子表达减少导致上皮细胞失去细胞间黏附作用；角蛋白为主的细胞骨架转变为波形蛋白为主的细胞骨架，并因此转化成纺锤体型细胞，虽然有时上皮间质转化发生了功能上的改变，但细胞形态并未随之发生改变[10]。上皮间质转化是极化的上皮细胞的基底膜通过其基底面相互作用，经过多次的生物化学变化，使它具有了间充质细胞的形态和特征，包括迁移能力的增强，具有侵袭能力，显著增加产生细胞外基质组分能力的生物学过程[11]。在上皮间质转化过程中，不动的、极性上皮细胞失去通过细胞-细胞嵌入式连接聚集成的细胞单元，而通过溶解细胞-细胞间的连接并转变成黏结松散断裂的单个细胞，并变为非极性的、运动型的和具有侵袭能力及抗凋亡能力的间质细胞[12-13]。肿瘤细胞发生转移后，在肿瘤细胞微环境因素的作用下，由上皮细胞经上皮间质转化转换而来的间质细胞可通过间质上皮转化再转化为上皮细胞，进而又获得具有上皮细胞表型特性的细胞，如 E-钙黏素表达的上调[14]。上皮间质转化可发生在正常生理过程和特定的病理过程中，根据其发生的生物学环境的不同而将其分为3种类型：1型，与多细胞生物体内胚胎植入，原肠胚形成、器官发育、神经细胞运动有关；2型，与创伤修复，组织再生，炎症和器官纤维化有关；3型，与癌细胞侵袭转移有关[11]。 2.2 上皮间质转化与干细胞诱导分化和肿瘤发生上皮间质转化涉及到细胞在体内和体外分化。脊椎动物是由无特定细胞类型的单细胞受精卵在子宫内继续分化发育而来，胚胎形成发育中第一次发生上皮间质转化的过程包括囊胚在子宫壁的着床、原肠胚和神经嵴的形成，而脊索、节体和泌尿生殖系统上皮性质组织的分化形成又依赖于上皮间质转化的逆过程间质上皮转化[2]。受精约5 d后的受精卵称为囊胚，囊胚在子宫壁中植入称为着床，囊胚中的一些细胞向囊胚腔内生长形成内细胞团，内细胞团经历上皮间质转化形成可发育构成机体所有细胞类型的内、中、外3个胚层，胚胎干细胞来自于内细胞团细胞；囊胚中一些细胞形成滋养外胚层，后续形成胎盘。iPSCs可通过向体细胞中导入与多能性相关的转录因子诱导细胞重编程，进而使其获得多能性。2007年Takahashi等通过用反转录病毒为载体将4种外源性转录因子C-myc、KLF4、Oct3/4、S0X2导入人皮肤成纤维细胞，诱导其重编程，成功获得了人iPSCs[15]。iPSCs的获得是间质上皮转化过程，在此过程中可观察到包括细胞形态、细胞代谢、细胞基因表达谱系及表观遗传状态等方面的改变[16]。绝大多数iPSCs是由成纤维细胞重编程而获得，成纤维细胞是典型的间充质细胞而iPSCs是上皮性质的细胞，所以iPSCs的获得必须要经历间质上皮转化过程才能实现[17-18]。iPSCs特性是在体内外均具有分化形成3个胚层的能力，进而可分化为构成机体的所有组织和细胞，而其实现分化的过程必须依赖上皮间质转化。iPSCs与胚胎干细胞有类似的生物学特性，包括细胞形态、生长特性及标志物[4]。鼠和人胚胎干细胞自发分化也被认为是上皮间质转化的类似事件，因分化过程中增加表达的Snail、Slug和TCF3均是上皮间质转化事件的诱导因子，且E-钙黏蛋白表达也切换到N-钙黏蛋白的表达[19]，人胚胎干细胞体外往定向内胚层分化过程中也会观察到E-钙黏蛋白表达降低并可观察到有N-钙黏蛋白表达[20]。来源于上皮细胞的恶性肿瘤称为癌，转移是癌症引起死亡的主要原因。上皮性质的癌细胞脱离原发肿瘤，侵入周围组织、血管或淋巴管是发生转移的首要步骤，上皮性质的癌细胞经上皮间质转化为具有更强侵袭力的间质性细胞，经血液或淋巴途径播散到其他部位再经间质上皮转化为上皮性质的细胞继续生长生成继发肿瘤[21]。有研究表明，在被肿瘤细胞浸润的周边组织中可检测到上皮间质转化相关基因的表达[22]。上皮间质转化是肿瘤细胞发生侵袭的关键，而侵袭是肿瘤细胞发生转移的前提。单纯上皮间质转化只会使细胞发生侵袭，并未形成真正的转移，因原发肿瘤细胞经上皮间质转化后已转变为间质特性的细胞，要在其他部位继续停留生长还需经间质上皮转化重新转变为上皮特性的细胞，所以认为上皮间质转化在增加肿瘤侵袭性的同时其实是在抑制肿瘤细胞的转移能力[23]。肿瘤干细胞是一类可以启动肿瘤发生和维持肿瘤细胞自我更新和不衰老生长特性的细胞[24]。只有一小类肿瘤细胞具有肿瘤干细胞特性，有学者通过在乳腺上皮细胞中过度表达转化因子Snail和 Twist诱导上皮间质转化发生，然后可在乳腺组织中发现肿瘤干细胞样表型的肿瘤细胞富集并具有间质特性，把这类和癌症干细胞表型相似的干细胞称癌干细胞样细胞[25-27]。Santisteban等通过乳腺上皮细胞癌免疫诱导上皮间质转化导致肿瘤在体内生长[28]。通过诱导非至瘤性和永生性乳腺上皮细胞经历上皮间质转化过程，发现乳腺细胞变成微球型结构并出现肿瘤启动能力，同时还发现间质特性标志物和癌干细胞标志(CD44+，CD24-)，表明上皮间质转化可能会使细胞产生干细胞特性[29]。 2.3 上皮间质转化分子机制上皮间质转化的发生受多种生长因子、转录因子、信号蛋白分子和细胞内转导信号通路的诱导和调节，目前的研究表明，有众多的miRNA 和表观遗传也参与细胞的上皮间质转化过程[30]。上皮间质转化相关的细胞外的信号分子可和细胞内信号转导通路、转录因子之间进行相互作用形成信号转导系统网，共同作用促进上皮间质转化的发生。 2.3.1 上皮间质转化与E-钙黏素 E-钙黏素的缺失是上皮间质转化的最重要标志[31]，钙黏素是上皮组织中的一类依赖Ca2+的细胞间跨膜黏连糖蛋白分子，主要参与细胞间的连接，分为E-钙黏素、P-钙黏素和N-钙黏素3种，其中E-钙黏素是上皮间质转化发生的关键分子，E-钙黏素的表达下调、抑制及功能丧失都可能会诱导上皮间质转化的发生，导致肿瘤的发生和转移[32]。E-钙黏素可与β-链环素和γ-链环素结合，再与α-连环素相连，形成E-钙黏素-β-链环素-α-链环素复合体[33]，此复合体再通过直接连接到肌动蛋白细胞骨架上介导细胞与细胞之间的黏附，用以细胞间黏附稳定性和细胞极性的维持，E-钙黏素还可通过蛋白质与胞内结构域相互作用直接或间接参与细胞的信号转导，对胚胎发育及肿瘤的发生、发展和转移具有重要作用[34]。CDH1基因转录表达E-钙黏蛋白，该基因的突变、DNA甲基化和转录抑制等都可能导致E-钙黏蛋白表达低下或丧失[35-36]。在癌症组织细胞中，E-钙黏素是最早且被高频率鉴定为可使启动子甲基化的基因之一[37]。癌症中，基因突变、翻译后修饰，如蛋白水解作用的异常加强或蛋白磷酸化及糖基化等的修饰异常，都可能导致E-钙黏素基因遗传及表观遗传改变，导致基因功能丧失或生产缺陷蛋白，诱发上皮间质转化[37]，进而促进上皮到间质的转化及癌细胞脱离原发部位转移在其它部位形成继发肿瘤。 2.3.2 上皮间质转化相关转录因子上皮间质转化的发生通常需先有上皮间质转化相关转录因子的激活[38]，作为上皮间质转化的表达标记物，Snail1(Snail)、Snail2(Slug)、Snail3、ZEB ( ZEB1、ZEB2)、Twist 等转录因子可在转录水平上调节E-钙黏素基因的表达，它们能竞争结合E-钙黏素基因启动子中的E-box序列，引起基因的表观遗传沉默，从而抑制E-钙黏蛋白的表达[39]，其中Snail1和Snail2与E-钙黏素基因启动子中E-boxde 序列的结合还可促进RhoB的形成并能抑制上皮标记物Cytokeratin-8、Mucin-1 的表达，诱导上皮间质转化的发生并增加癌细胞的侵袭和转移能力[40]。转录阻遏因子更强诱导上皮间质转化的作用，能促进转录因子Snail的表达[41]，这也表明Twist和Snail可形成正反馈作用下调E-钙黏素的表达，促进上皮间质转化的发生，促进癌细胞的侵袭及转移，有研究表明Twist2诱导上皮间质转化的作用比Twist1更强[42]。 2.3.3 上皮间质转化相关生长因子及相关信号通路与上皮间质转化相关的生长因子可与细胞细胞表面的受体结合，通过相应信号转导通路激活细胞内相关转录因子来调节上皮间质转化的发生，进而影响干细胞的分化和肿瘤细胞的浸润转移。除了在肿瘤细胞相关的上皮间质转化中发挥作用外，这些生长因子还起调节机体作用的其他生理功能，如细胞增殖、生长、分化，其具体特性功能取决于周边微环境中不同的信号分子与这些因子的相互作用。经实验验证这些生长因子主要包括：转化生长因子β家族、肝细胞生长因子、表皮生长因子、胰岛素样生长因子、血管内皮生长因子、血小板衍生生长因子、前列腺素E2等。目前研究比较透彻的在调节干细胞分化及肿瘤发生转移相关的上皮间质转化的信号途径有转化生长因子β、Notch、Wnt 、Hedgehog、Hippo等。有研究显示，转化生长因子β与Notch、Wnt、相互作用可引起显著的上皮间质转化[43]。转化生长因子β信号通路与上皮间质转化：转化生长因子β家族是众多诱导胚胎发育过程中上皮间质转化相关生长因子中被研究最透彻的因子[44]。有研究显示，转化生长因子β信号通路对维持成体干细胞及胚胎干细胞的自我更新及分化发挥重要作用[45]，调控初始阶段的胚胎干细胞胚层定向分化。胚胎干细胞具有多向分化的潜在能力，成体干细胞也具有不同的分化潜能故其可被分为单能干细胞和多能干细胞，如心肌干细胞只能分化出单一类型的心肌细胞，造血干细胞可分化出红细胞、血小板、巨噬细胞等多种类型的细胞。转化生长因子β已被证明是诱导上皮间质转化发生的重要的蛋白分子，转化生长因子β主要是通过与细胞表面的转化生长因子β受体结合，实现跨膜信号转导来影响靶基因转录和表达，从而发挥调节细胞的增殖、生长和分化、凋亡及自噬等生化功能。具体机制主要是转化生长因子β受体是跨膜的丝氨酸/苏氨酸蛋白激酶，Ⅱ型膜受体与转化生长因子β结合后导致Ⅱ型受体的构象改变从而结合Ⅰ型受体并使其磷酸化具有活性。活化的Ⅰ型受体进一步磷酸化胞质中的靶蛋白Smad，磷酸化的Smad与Smad4结合后转入细胞核与相应的DNA或影响DNA的蛋白结合来发挥其调节靶基因的功能。近期有研究表明，糖药病治疗药甲福明可起到抑制转化生长因子β1 的作用[46]。 Wnt/β-catenin信号通路与上皮间质转化：Wnt/ β-catenin信号通路是复杂的Wnt信号通路中经典的信号通路，在调控干细胞增殖、分化相关上皮间质转化中具有重要作用。Wnt信号在调节神经干细胞的分化作用中具“两面性”，神经干细胞未被分化出之前 Wnt/ β-catenin可抑制胚胎干细胞向其分化，一旦神经干细胞分化开始Wnt/β-catenin又可促进分化过程中早期神经脊干细胞分化为感觉神经元。Wnt信号通过与细胞表面的LRP5/6受体结合来减少APC-Axin复合物的生成，进而减少GSK-3β对细胞内β-catenin的磷酸化及β-catenin的降解，细胞质中堆积的β-catenin与转录因子结合并转入细胞核促进AP-1、c-Myc等靶基因的表达[47]。在上皮间质转化过程中β-catenin的磷酸化导致其从E-钙黏素上脱落并定位到细胞核，在细胞核中与Tcf转录因子一起调节促侵入性基因的表达[12]。Wnt/β-catenin在诱导干细胞分化及肿瘤细胞的浸润、转移过程中的复杂及重要作用值得做更深入的研究。 Hippo信号通路与上皮间质转化：Hippo/YAP信号通路的发现与其他通路相比较晚，在干细胞的分化调控及癌症的发生中具有重要作用[48]。Hippo信号通路最早被发现是在果蝇体内，且是一条抑制细胞生长且高度保守的通路。YAP1是Hippo通路中经典的下游分子之一，通过结合并激活一些转录因子的表达来调节下游靶基因的表达[49]。LATS1/2激酶可磷酸化Hippo等位基因TAE及下游效应分子YAP，磷酸化后的TAE、YAP定位于细胞质中，并与14-3-3蛋白相互作用。Hippo通路的活化抑制YAP1的表达并使其去磷酸化，若上游分子及失活则YAP、TAZ转至细胞核，活化调控基因的表达[50]。在胚胎干细胞发育过程中Hippo信号通路抑制细胞重编程，调控内细胞团从滋养外胚层的分离。在结肠癌信号通路系统中，Hippo与Wnt/β-catenin信号通路相互作用调节癌细胞的发生与进展。YAP1可与β-catenin形成复合物从而调节Wnt/β-catenin通路的活化，Hippo下游效应分子TAZ又同时是Wnt/β-catenin转录共激活因子。 miRNAs与上皮间质转化：miRNAs是一种内源性非编码单链RNA，通过与相应的mRNA互补结合来阻遏蛋白质的翻译或引起mRNA的降解，从而负性调控转录后水平基因表达。由此可见，miRNAs是调控基因表达的重要组成部分之一。干细胞分化主要表现在其形态结构和生物学功能的改变，而引起这些改变的最根本的原因却还是基因改变影响相关信号分子、信号通路，信号分子、信号通路又作用于相应靶基因序列，从而形成复杂的基因、基因产物之间相互作用网。Let-7家族对于干细胞的分化及肿瘤细胞的发生、侵袭、转移都发挥重要的调节作用。miRNA可通过调节上皮间质转化相关基因和转录因子的表达来促进或抑制上皮间质转化过程。一些miRNA可通过调节E-钙黏素的表达来直接或间接调节上皮间质转化的发生，如Zeb-1和Zeb-2的表达可被miRNA-200和miRNA-205抑制，Zeb-1和Zeb-2又通过抑制E-钙黏素的表达来促发上皮间质转化，诱导癌细胞的侵袭转移，而Zeb-1和Zeb-2却也可以反过来抑制 miR-200家族的表达，从而部分逆转发生间质上皮转化，由此可见Zeb基因家族与miR-200家族可相互负性调节，形成了双重的调节通路。miRNA-9则可直接抑制E-钙黏素基因表达并激活β-catenin信号来抑制上皮间质转化的发生。一些miRNA对上皮间质转化的调节具有组织特异性，有研究表明，高表达的miRNA能抑制人宫颈癌中的Caski细胞发生由表皮生长因子所诱导的上皮间质转化，且对化疗药物DDP的治疗效果有很大提升。然而有学者在乳腺上皮细胞中通过转化生长因子β来诱导提高miR-155的表达，然后发现因靶向抑制了RhoA的表达下促使了上皮向间质的转化。"

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Role of epithelial-mesenchymal transition in stem cell differentiation and tumorigenesis

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